Protein import into and across the mitochondrial inner membrane: role of the TIM23 and TIM22 translocons

Jensen, Robert E.; Dunn, Cory D.

doi:10.1016/s0167-4889(02)00261-6

Cited by 116 publications

(104 citation statements)

References 81 publications

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“…However, Taz1 could be imported into yeast mitochondria independent of the inner membrane potential. Because protein translocation across the inner membrane strictly requires the ⌬ , this finding indicated that the protein was not transported across the inner membrane (Neupert, 1997;Jensen and Dunn, 2002;Koehler, 2004;Rehling et al, 2004). This was corroborated by cell fractionation analyses, which showed that Taz1 was an integral membrane protein of the outer mitochondrial membrane that exposed its soluble Cterminal domain into the intermembrane space.…”

Section: Discussionmentioning

confidence: 82%

“…Dissociation of the membrane potential (⌬ ) before import by the addition of the K ϩ -ionophore valinomycin in the presence of K ϩ in the buffer did not affect transport of the precursor to a protease-protected location ( Figure 1B, lane 6). Because protein transport across the inner mitochondrial membrane depends on ⌬ (Neupert, 1997;Jensen and Dunn, 2002;Koehler, 2004;Rehling et al, 2004), we concluded that Taz1 was not transported across the inner membrane.…”

Section: Import Of Taz1 Into S Cerevisiae Mitochondriamentioning

confidence: 90%

“…However, these techniques did not elucidate the mitochondrial compartment in which the protein was located. Typically, proteins that are destined for the mitochondrial matrix and some inner membrane proteins possess cleavable amino-terminal targeting signals (presequences; Neupert, 1997;Jensen and Dunn, 2002;Rehling et al, 2004). However, neither visual nor computer inspection of the primary structure of the proteins identified a predictable presequence.…”

Section: Import Of Taz1 Into S Cerevisiae Mitochondriamentioning

confidence: 99%

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Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Brandner

Mick

Frazier

et al. 2005

MBoC

190

150

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The Saccharomyces cerevisiae Taz1 protein is the orthologue of human Tafazzin, a protein that when inactive causes Barth Syndrome (BTHS), a severe inherited X-linked disease. Taz1 is a mitochondrial acyltransferase involved in the remodeling of cardiolipin. We show that Taz1 is an outer mitochondrial membrane protein exposed to the intermembrane space (IMS). Transport of Taz1 into mitochondria depends on the receptor Tom5 of the translocase of the outer membrane (TOM complex) and the small Tim proteins of the IMS, but is independent of the sorting and assembly complex (SAM). TAZ1 deletion in yeast leads to growth defects on nonfermentable carbon sources, indicative of a defect in respiration. Because cardiolipin has been proposed to stabilize supercomplexes of the respiratory chain complexes III and IV, we assess supercomplexes in taz1⌬ mitochondria and show that these are destabilized in taz1⌬ mitochondria. This leads to a selective release of a complex IV monomer from the III 2 IV 2 supercomplex. In addition, assembly analyses of newly imported subunits into complex IV show that incorporation of the complex IV monomer into supercomplexes is affected in taz1⌬ mitochondria. We conclude that inactivation of Taz1 affects both assembly and stability of respiratory chain complexes in the inner membrane of mitochondria. INTRODUCTIONBarth Syndrome is an X-linked recessive disorder that is characterized by cardioskeletal myopathy, neutropenia, increased urine levels of 3-methylglutaconic acid, abnormal mitochondria, and respiratory chain dysfunction (Barth et al., 1983(Barth et al., , 1996Kelley et al., 1991;D'Adamo et al., 1997). The disease is often fatal in infancy and early childhood because of cardiac failure and bacterial infections (Barth et al., 2004). Bione et al. (1996) identified the gene responsible, termed Tafazzin (TAZ), and localized it to region q28 on the X chromosome. Sequence analyses demonstrate that the Taz protein is highly conserved from yeast to man and that it displays sequence similarity to acyltransferases that participate in the metabolism of phospholipids (Neuwald, 1997). Phospholipid analyses of fibroblasts from patients and yeast taz1⌬ mutant cells show reduced cardiolipin levels and an altered acyl chain composition (Vreken et al., 2000;Vaz et al., 2003;Xu et al., 2003;Gu et al., 2004).Cardiolipin is formed by two glycerol-linked phosphatidyl moieties. The four acyl side chains are usually monoand di-unsaturated fatty acids in higher eukaryotes. Remodeling of cardiolipin through a cycle of deacylation and successive reacylation leads to the final and specific acyl composition. In heart and skeletal muscle mitochondria the tetralinoleoyl species predominates Xu et al., 2003;Hatch, 2004). Cardiolipin is primarily found in the mitochondrial membranes of eukaryotes (Hoch, 1992) and the bacterial cytoplasmic membrane. Although the molecular function of cardiolipin is still unclear, several studies have suggested that it is required for the proper function of some proteins and protein complexe...

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Section: Discussionmentioning

confidence: 82%

Section: Import Of Taz1 Into S Cerevisiae Mitochondriamentioning

confidence: 90%

Section: Import Of Taz1 Into S Cerevisiae Mitochondriamentioning

confidence: 99%

See 1 more Smart Citation

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Brandner

Mick

Frazier

et al. 2005

MBoC

190

150

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“…The pathways along which these proteins are sorted in the IMS are diverse (1)(2)(3)(4)(5). Precursors of proteins containing cleavable matrix targeting sequences followed by transmembrane segments are initially using the general import pathway mediated by the TIM23 (translocase of the inner membrane 23) complex until the transmembrane segment reaches the inner membrane where it undergoes translocation arrest.…”

mentioning

confidence: 99%

Functional Characterization of Mia40p, the Central Component of the Disulfide Relay System of the Mitochondrial Intermembrane Space

Grumbt

Stroobant

Terziyska

et al. 2007

Journal of Biological Chemistry

116

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Mia40p and Erv1p are components of a translocation pathway for the import of cysteine-rich proteins into the intermembrane space of mitochondria. We have characterized the redox behavior of Mia40p and reconstituted the disulfide transfer system of Mia40p by using recombinant functional C-terminal fragment of Mia40p, Mia40C, and Erv1p. Oxidized Mia40p contains three intramolecular disulfide bonds. One disulfide bond connects the first two cysteine residues in the CPC motif. The second and the third bonds belong to the twin CX 9 C motif and bridge the cysteine residues of two CX 9 C segments. In contrast to the stabilizing disulfide bonds of the twin CX 9 C motif, the first disulfide bond was easily accessible to reducing agents. Partially reduced Mia40C generated by opening of this bond as well as fully reduced Mia40C were oxidized by Erv1p in vitro. In the course of this reaction, mixed disulfides of Mia40C and Erv1p were formed. Reoxidation of fully reduced Mia40C required the presence of the first two cysteine residues in Mia40C. However, efficient reoxidation of a Mia40C variant containing only the cysteine residues of the twin CX 9 C motif was observed when in addition to Erv1p low amounts of wild type Mia40C were present. In the reconstituted system the thiol oxidase Erv1p was sufficient to transfer disulfide bonds to Mia40C, which then could oxidize the variant of Mia40C. In summary, we reconstituted a disulfide relay system consisting of Mia40C and Erv1p.

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“…In the first of these translocons, Tim23 forms a narrow channel across the inner membrane wide enough to allow passage of a single unfolded polypeptide, in a process energized by the membrane potential and the ATP-regulated actions of matrix-localized mitochondrial hsp70. (23)(24)(25) In the Tim22-based TIM translocon, polytopic membrane proteins are transferred through a Tim23-sized channel formed by Tim22, (26) integrating each successive transmembrane domain that it encounters into the membrane (27) by a mechanism that relies on the membrane potential alone. Proteins destined to cross the chloroplast inner membrane travel through the TIC translocon, although the working of this translocon are presently not well understood.…”

Section: Introductionmentioning

confidence: 99%

Move it on over: getting proteins across biological membranes

Eichler¹,

Irihimovitch²

2003

BioEssays

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SummaryThe translocation of proteins across membranes is a central problem in biology. Regardless of the system in question, delivering proteins across a given membrane relies on many of the same basic themes. At the same time, however, each membrane translocation system, be it signal-gated or signal-assembled, makes use of components unique to that system. The latest findings on protein translocation across a variety of biological membranes have been presented in a recent review article. (1)

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Protein import into and across the mitochondrial inner membrane: role of the TIM23 and TIM22 translocons

Cited by 116 publications

References 81 publications

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Functional Characterization of Mia40p, the Central Component of the Disulfide Relay System of the Mitochondrial Intermembrane Space

Move it on over: getting proteins across biological membranes

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